Novel 3-substituted 4-hydroxycoumarins and their process of preparation



NOVEL 3-SUBSTITUTED 4-HYDROXYCOUMARINS AND THEIR PROCESS OF PREPARATION Kurt Wilhelm Knoevenagel, Kleinkarlbach, Rheiupfalz,

ermauy, assiguor to N orddeutsch Aflinerie, Hamburg,

Germany, a corporation of Germany, and C. F. Spiess & Sohn, Kleinkarlbach, Rheinpfalz, Germany, a firm N Drawing. Application August 23, 1954, Serial No. 451,673

6 Claims. (Cl. 260-3431) The present invention relates to novel 3-substituted 4- hydroxycoumarins and their process of preparation.

3-substituted 4-hydroxyc oumarins of various types have already been prepared by condensing 4-hydroxycoumarins with certain unsaturated ketones in a Michael-type reaction.

know has been found that substituted ketoesters of the following general formula R2-orr=o coon,

in which R1 represents a methyl or ethyl group and R2 represents a lower alkyl group or a phenyl group will react with 4-hydroxycoumarin in a Michael-type reaction to produce new S-substituted 4-hydroxycoumarins having useful properties.

The new 3-substituted 4-hydroxycoumarins which are obtained in this manner have the following general formula:

Di-keto-t'orm in which R1 represents a methyl or ethyl group and R2 represents an alkyl group, phenyl group or substituted phenyl group. By a keto-enol transformation these 3- substituted 4-hydroxycoumarins may in part exist in the corresponding two keto-enolforms and in the corresponding di-enolform which have the following formulaez.

Enol-keto-form Keto-enol-form United States. Patent 0 2,743,283. Patented Apr. 24, 1956 Di-enol-form COORl For the sake of simplicity, only the formula for the diketoform will be used in this application but it is intended that the other three formulae mentioned above also be included. Our new 3-substituted 4-hydroxycoumarins can be produced by a Michael-type addition reaction represented by the following equation:

The reaction can be carried out by refluxing the reactants in an inert solvent or by melting the reactants together. It is advantageous to use a small amount of an alkaline substance, such as, for instance, pyridine or alkalimetah alcoholate or sodiumphosphate or potassiumphosphate as catalysts. It is also advantageous to carry out the reaction with heating as, for instance, by refluxing the reactants in an inert solvent. It is also advantageous to reflux to lower the capillary resistance when mixed with a bait in a concentration of 0.01 to 0.03% and fed to animals.

Example 1 10 g. benzalethylacetoacetate were refluxed for 4 hours with 7.4 g. 4-hydroxycoumarin and 0.5 g. sodiumphosphate in com. water. After cooling the solid product was recovered by filtration and was recrystallizedfrom amixture of 3 parts acetone with 1 part water. The at acetyl ,6 phenyl ,8 hydroxycoumarinyl' propionatewas obtained in the form of white crystals with a melting point of 149-151 C. It is soluble in acetone and substantially insoluble in cold water; and dissolves in alkaline solutions with formation of the corresponding salt. The yield is about 25%.

19.94 com. 11/ 10 NaOH were required for titration 0.760 g. of the substance (calculated 20.00 ccm.). Analysis of the final product indicated the formula CazHzoOs;

Carbon: Calculated, 69.46%; found, 69.42%. Hydrogen: Calculated, 5.30%; found, 5.33%.

Upon recrystallization from toluol or benzene in the presence. of. water ecompound. was. re o red. a

hydrate with the following formula:

The hydrate is a light yellow solid substance which melts at 114-116 C. The hydrate is soluble in acetone and substantially insoluble in cold water and is soluble in dilute alkalies to salt. 1

:00 ccm. of n/ 10 NaOH are required for titration- 0.796 g. of the substance (calculated 20.00 ccm.-).

Analysis of the hydrateform indicated the formula Carbon: Calculated, 66.30%; found. 66.62%. Hydrogen: Calculated, 6.03% found, 5.59%

When the hydrate was recrystallized from; acetonewater the free substance with the melting point of 149- 151 C. was obtained again.

The a acetyl B phenyl ethylpropionate, as well as the hydrate, is saponified upon refluxing in alkaline solutions and with formation of the 3(l-phenyl-Z-acetyl)-ethyl-4-hydroxycoumarin which can be isolated with a melting point of 162 C.

- p" hydroxycoumarinyl- Example 2 Example 3 distilled;

26.5 g. 4-hydroxycoumarinand 2 g. pyridine. were re tluxed with 170g. dioxane. During aperiod of-t4 hours.

34.7 g. benzalethylacetoacetate. dissolved in g. dioxane.

were. dropped into the mixture. The. reaction-mixture: was refluxed for a further /2 hour. added and the dioxane was distilled off underreduced pressure. The residue was timesand recrystallized from- -toluo1.. Ansolid. white substance was. obtained, which could be, if.=necessary,-.

recrystallized. from acetone-watea. Melting point.-149?r C., yield Example 4 26.5 g., 4-hydroxycoumarin, and, 2,. g... potassium-. g dioxane... Duriugaphosphatewere refluxedwith 70 periodoi 4 hours 34.7 gbenzalethylacetoacetate,dis:

so1ved.in 30 g. dioxane. were dropped.intotheumixturea a f rther /2 hQLlR' Then 1.8. g. P5105, were addedand thedioxane. was; dis-Qv tilledofi under reduced pressure. The residue .wasw-ashed. with water several times -and recrystallized from acetone-.1

The reaction-.rnixture :was. refluxedifor water. Product, and yield. about. the same. as in. Exarna ple 2.

Example 5 128 g. 4-hydroxycoumarin-and 5 g. sodiumphosphate were refluxed witlr- 100 com; toluol. of 3 /2 hours 150 g. benzalethylacetoacetate dissolved in; ccm.v toluolwere droppeddn. refluxing for another /2 form solutions ofthe corresponding /2 hour. Then.

The. residue was. washed obtained, which could.be,. if. Melting Then 1.8 g. P205 were.

washed with water several.

During a periodwhich-were Afterhour the hot solution was filtered.

After cooling a light-yellow solid substance was sepaa edbx ion-.1 he p pdu t s. shsda ysra times with toluol and, if necessary, recrystallized from acetone-water. The yield was about 35%. The product melted at about 150 C.

Example- 6 128 g. 4-hydroxycoumarin, 150g. benzalethylacetoacetate and- 5 grsodiumphosphate were melted for- 1 /2 hours. at C. whilestirring. Thehot residue was, dissolved in hot toluol.,and filtered. After cooling the lightyellow;solid substance was separatedby filtration and .was recrystallizedfrom acetone-water. Theyield was about26%.. The product melted at about. 149 C.

I claim:

1. A 3-substituted 4'hydroxyc0umarin of the general formula C O 0R1 CH Gil-i111; 5 1

in which Rr is a lower unsubstituted ,alkyl group and R2 is a phenyl group.

2. A 3-substituted. 4-hydroxycouinarin in accordance with claim 1 in which R1 is. ethyl.

3. A 3-substituted 4-hydroxycoumarin-hydrate of the general formula HO CH1 COORI in which R1 represents a lower unsubstituted alkyl group.

and R2 a phenyl group.

4. A 3-substituted 4-hydroxycoumarin in accordance with claim 3 in which R1 is ethyl.

5. A process of producing 3-substituted 4-hydroxycoumarins of the following general formula in which R1 isa lower unsubstituted alkyl group-andRz aphenylgroup which consists in condensing. 4-hydroxy' coumarinwith a substituted 3 general formula:

COORi Rr-OH=C CO--CHa in which R1 and R2 have the same meaning as above.

6. A process of producing B-substituted 4-hydroxycoumarins as set forth in claim 5 in which R1 is ethyl.

References Cited in the file of this patent UNITED STATES PATENTS 2,427,578 Stahmann et a1 Sept. 16, 1947 FOREIGN PATENTS 568,858 Great Britain Apr. 24, 1945 884,500 Germany July 27, 1953 OTHER REFERENCES Mohlo et al.: Compt. rendu, vol., 223, pp. 1141-42 Trenknerowna, Chem. Abst, vol... 31, p. 2187 (1937).

ketoester of the following. 

1. A 3-SUBSTITUTED 4-HYDROXYCOUMARIN OF THE GENERAL FORMULA 